Many muscular dystrophies are caused by mutation in proteins that compromise the stability and integrity of the muscle sarcolemma, which results in high serum level of muscle enzymes such as Creatine Kinase. Understanding the mechanism by which healthy myofibers maintain their sarcolemmal integrity would enable development of new therapies for these muscular dystrophies. Miyoshi myopathy (MM) and limb girdle muscular dystrophy (LGMD) 2B, caused by mutations in dysferlin gene are such diseases. We have identified that loss of sarcolemmal integrity in LGMD2B muscle fibers is due to the delay in fusion of lysosome with the injured sarcolemma. This causes a delay in injury-triggered secretion of the lysosomal enzyme acid sphingomyelinase. Providing extracellular sphingomyelinase reverses the repair deficit and offers a potential therapy for LGMD2B. However, the mechanism by which alteration in sphingomyelin and other cell membrane lipids facilitates repair of injured muscle cell membranes has not been fully elucidated. This proposal aims to identify how lipids and lipid modifying enzymes such as acid sphingomyelinase facilitate maintenance of sarcolemmal integrity and facilitate repair of injured sarcolemma. We will achieve this by visualizing and modifying lipid composition of healthy muscle cell membrane and assess their effect on sarcolemmal integirty. We will also assess how lipids respond are altered in the LGMD2B patient and mouse muscle cells to identify potential therapeutic interventions to address these alterations. One such intervention we have established is the use of acid sphingomyelinase and we will evaluate its preclinical therapeutic potential for LGMD2B. These studies will not only help understand the role of lipids in maintenance of sarcolemmal integrity, but also provide insight into developing novel therapies for muscular dystrophies that move beyond targeting the proteins to also targeting the sarcolemmal lipids.

Public Health Relevance

There is little understanding of the mechanism underlying the role of sarcolemmal lipids in facilitating muscle cell membrane repair. The studies proposed here is the first concerted effort to elucidate how sarcolemmal lipids respond to injury and harness this knowledge to develop novel therapies for muscular dystrophies such as LGMD2B that are associated with reduced sarcolemmal integrity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
2R01AR055686-07A1
Application #
9384104
Study Section
Skeletal Muscle and Exercise Physiology Study Section (SMEP)
Program Officer
Cheever, Thomas
Project Start
2008-07-02
Project End
2022-06-30
Budget Start
2017-08-01
Budget End
2018-06-30
Support Year
7
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Children's Research Institute
Department
Type
DUNS #
143983562
City
Washington
State
DC
Country
United States
Zip Code
20010
Sreetama, Sen Chandra; Chandra, Goutam; Van der Meulen, Jack H et al. (2018) Membrane Stabilization by Modified Steroid Offers a Potential Therapy for Muscular Dystrophy Due to Dysferlin Deficit. Mol Ther 26:2231-2242
Defour, Aurelia; Medikayala, Sushma; Van der Meulen, Jack H et al. (2017) Annexin A2 links poor myofiber repair with inflammation and adipogenic replacement of the injured muscle. Hum Mol Genet 26:1979-1991
Horn, Adam; Van der Meulen, Jack H; Defour, Aurelia et al. (2017) Mitochondrial redox signaling enables repair of injured skeletal muscle cells. Sci Signal 10:
Vila, Maria C; Rayavarapu, Sree; Hogarth, Marshall W et al. (2017) Mitochondria mediate cell membrane repair and contribute to Duchenne muscular dystrophy. Cell Death Differ 24:330-342
Sreetama, S C; Takano, T; Nedergaard, M et al. (2016) Injured astrocytes are repaired by Synaptotagmin XI-regulated lysosome exocytosis. Cell Death Differ 23:596-607
Leikina, Evgenia; Defour, Aurelia; Melikov, Kamran et al. (2015) Annexin A1 Deficiency does not Affect Myofiber Repair but Delays Regeneration of Injured Muscles. Sci Rep 5:18246
Scheffer, Luana L; Sreetama, Sen Chandra; Sharma, Nimisha et al. (2014) Mechanism of Ca²?-triggered ESCRT assembly and regulation of cell membrane repair. Nat Commun 5:5646
Defour, Aurelia; Sreetama, S C; Jaiswal, Jyoti K (2014) Imaging cell membrane injury and subcellular processes involved in repair. J Vis Exp :
Defour, A; Van der Meulen, J H; Bhat, R et al. (2014) Dysferlin regulates cell membrane repair by facilitating injury-triggered acid sphingomyelinase secretion. Cell Death Dis 5:e1306
Jaiswal, Jyoti K; Lauritzen, Stine P; Scheffer, Luana et al. (2014) S100A11 is required for efficient plasma membrane repair and survival of invasive cancer cells. Nat Commun 5:3795

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